MET Alterations and the Molecular Landscape of NSCLC

A pathology report that simply states “MET-positive” may not provide sufficient information to guide clinical interpretation in non-small cell lung cancer (NSCLC). As biomarker-directed treatment continues to refine NSCLC management, oncologists are increasingly challenged to interpret a growing range of molecular and protein-based findings.¹ The reason is that the term “MET-positive” encompasses multiple forms of mesenchymal-epithelial transition (MET) dysregulation that reflect distinct biological findings, require different testing methodologies, and may carry different therapeutic implications.² Understanding which MET biomarker is being evaluated and selecting the testing approach best suited to answer the clinical question is therefore essential for accurate interpretation.²   

Clinically relevant MET findings may include MET exon 14 skipping mutations, MET amplification, c-Met protein overexpression, and MET gene fusions.³ These MET aberrations are not interchangeable. MET exon 14 skipping and gene fusions represent DNA- or RNA-level alterations, while MET amplification reflects copy-number changes.^2-4 Additionally, MET protein overexpression represents changes in expression at the tumor cell surface.² A nonspecific “MET-positive” result may obscure important distinctions unless the report clearly indicates the biomarker category, analyte, testing method, and interpretive threshold.² Understanding these distinctions allows clinicians to select testing methods based on the clinical question rather than viewing MET as a single biomarker.²  

This distinction is especially important when selecting among next-generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH).² Before ordering MET testing, clinicians should consider four practical questions: 

• What biomarker am I looking for? 

• What analyte needs to be measured? 

• Which assay measures it? 

• How will the result influence clinical decision-making? 

Each testing method answers a different clinical question. NGS can identify DNA- or RNA-level alterations, including MET exon 14 skipping mutations and gene fusions.^2-4 IHC assesses c-Met protein expression in tumor cells and may report staining intensity and distribution.^2,3 FISH evaluates MET gene amplification and can help characterize amplification patterns.³ For medical oncologists, the key question is not simply whether a test returns a “MET-positive” result, but whether the selected assay aligns with the specific MET alteration of interest and provides information that can appropriately inform interpretation, tissue use, and next steps.²  

Biomarker assay selection also has practical implications because many NSCLC specimens are small, and sequential single-marker testing can quickly exhaust available tissue.^1,5 Selecting the most informative assay up front can help conserve tissue, minimize unnecessary testing, and reduce delays in obtaining clinically interpretable results.¹  

Interpreting a MET report requires attention to clinical context. For example, when reviewing a pathology report describing a tumor as “MET-positive,” clinicians should first determine whether the finding represents protein overexpression, gene amplification, MET exon 14 skipping, or another MET alteration before interpreting its significance. The report should also be reviewed to confirm the specific biomarker identified, the analyte tested, the method used, and the threshold or scoring system applied.² This is important because cutoffs and reporting language can vary across biomarker categories and assay types.² A MET alteration identified at diagnosis may have different implications than one emerging after targeted therapy, where acquired resistance may be part of the clinical picture.² Likewise, results from archived tissue may not fully reflect current tumor biology following intervening therapy.  

Ultimately, MET testing should be interpreted through a biomarker-specific framework rather than a nonspecific “MET-positive” designation. Understanding which assay was used, what it measured, and how the result fits the patient’s disease course can help oncologists translate MET biomarker information into more meaningful clinical decisions. Selecting the correct assay is not simply a laboratory decision; it is a clinical decision that determines what biological question is being answered.

1. Ascierto PA, Bifulco C, Palmieri G, Peters S, Sidiropoulos N. Preanalytic variables and tissue stewardship for reliable next-generation sequencing (NGS) clinical analysis. J Mol Diagn. 2019;21(5):756-767. doi:10.1016/j.jmoldx.2019.05.004.  

2. Saw SPL, Li MSC, Park S, et al. Targeting MET in EGFR-mutated NSCLC. J Thorac Oncol. 2026. Article 103711. doi:10.1016/j.jtho.2026.103711.  

3. Han Y, Yu Y, Miao D, et al. Targeting MET in NSCLC: an ever-expanding territory. JTO Clin Res Rep. 2024;5(2):100630. doi:10.1016/j.jtocrr.2023.100630.  

4. Sun D, Xing X, Wang Y, Hou H. MET fusions are targetable genomic variants in the treatment of advanced malignancies. Cell Commun Signal. 2024;22:20. doi:10.1186/s12964-023-01454-0.  

5. Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021;22(16):8661. doi:10.3390/ijms22168661.